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Can we stop progression of ankylosing spondylitis?

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Ankylosing spondylitis is characterised by inflammation of the spine and the entheses followed by bone formation. Excessive bone formation in ankylosing spondylitis leads to the formation of bone spurs, such as syndesmophytes and enthesiophytes, which contribute to ankylosis of joints and poor physical function. This process is based on increased differentiation of osteoblasts from their mesenchymal precursors, which allows to rapidly build up new bone. Prostaglandins, bone morphogenic proteins and Wnt proteins play an essential role in this process. By contrast, tumour necrosis factor (TNF) does not appear to be the direct trigger for osteophyte formation in ankylosing spondylitis. The article reviews the current knowledge regarding the mechanisms and clinical role of ankylosis and explains strategies on how to prevent it in patients with ankylosing spondylitis.

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease of unknown origin affecting the axial skeleton including the sacroiliac (SI) joints and the spine and also the peripheral joints and the entheses [1]. Since AS usually starts in the third decade, it affects people for most of their life. AS has a strong genetic component, with HLA-B27 being the most relevant gene. Clinically, pain and stiffness in the back are the leading complaints. In addition, the patient may suffer from peripheral joint pain or enthesitis, typically of the heel, or from bouts of uveitis. With time, bony ankylosis of the SI joints and the spine develops in many patients. Bony ankylosis at the spine may affect the vertebral bodies (syndesmophyte formation) as well as the facet, the zygapophyseal and the costovertebral joints. It is particularly spinal ankylosis, which results in loss of spinal mobility and changes in posture such as the development of thoracic kyphosis and irreversible stiffness. In a large proportion of patients, the disease course in AS that runs is fluctuating with not only periods of flares but also periods of remission or low disease activity. Some patients, however, suffer from persistently high disease activity.

Section snippets

Excessive bone apposition in AS

Bony overgrowth in AS has traditionally been considered as a structural damage arising from chronic immune activation and inflammation. In contrast to rheumatoid arthritis, where structural changes are of primarily catabolic nature, resulting in a net loss of bone substance in the vicinity of joints, structural changes in AS are dominated by anabolic processes. Bony spur formation, which arises from the cortical bone surface, is a common feature of AS and virtually affects all skeletal

Cellular and molecular mechanisms of bone formation in AS

A better insight into the molecular regulation of new bone formation is key for defining the optimal intervention strategies to retard or block bony ankylosis in patients with AS. Ankylosis in AS is based on the apposition of new bone along periosteal skeletal sites requiring differentiation of osteoblasts, which are the bone-forming cells. Osteoblasts develop from mesenchymal cell precursor cells, which cover the inactive periosteal bone surface. Growth as well as injury, such as observed

Acknowledgements

GS' work is supported by the Deutsche Forschungsgemeinschaft DFG (SFB643, SPP1468, FOR661), the Bundesministerium für Forschung und Bildung BMBF (project ANKYLOSS), the European Union projects Masterswitch, Kinacept and Adipoa, the Interdisziplinäres Zentrum für Klinische Forschung Erlangen and the Spondyloarthritis Immunology Reserach Alliance (SpIRAL).

References (47)

  • H. Samoto et al.

    Prostaglandin E2 stimulates bone sialoprotein (BSP) expression through cAMP and fibroblast growth factor 2 response elements in the proximal promoter of the rat BSP gene

    The Journal of Biological Chemistry.

    (2003 Aug 1)
  • M. Semënov et al.

    SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor

    The Journal of Biological Chemistry.

    (2005)
  • J. Sieper et al.

    Ankylosing spondylitis: an overview

    Annals of the Rheumatic Diseases

    (2002 Dec)
  • B. Cruickshank

    Lesions of cartilaginous joints in ankylosing spondylitis

    The Journal of Pathology and Bacteriology

    (1956 Jan)
  • X. Zhang et al.

    Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair

    The Journal of Clinical Investigation

    (2002 Jun)
  • V. Rosen

    BMP and BMP inhibitors in bone

    Annals of the New York Academy of Sciences

    (2006 Apr)
  • R.J. Lories et al.

    Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis

    Arthritis and Rheumatism

    (2006)
  • R. Baron et al.

    Minireview: targeting the Wnt/ß-catenin pathway to regulate bone formation in the adult skeleton

    Endocrinology

    (2007)
  • D. Diarra et al.

    Dickkopf-1 is a master regulator of joint remodeling

    Nature Medicine

    (2007)
  • S. Uderhardt et al.

    Blockade of Dickkopf-1 induces fusion of sacroiliac joints

    Annals of the Rheumatic Diseases

    (2009 Mar 26)
  • H. Appel et al.

    Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis

    Arthritis and Rheumatism

    (2009 Nov)
  • D.R. Bertolini et al.

    Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors

    Nature

    (1986 Feb 6-12)
  • C. Vincent et al.

    Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts

    Journal of Bone and Mineral Research.

    (2009 Aug)
  • S.H. Ralston et al.

    Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis

    BMJ

    (1990)
  • H. Appel et al.

    Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis

    Arthritis and Rheumatism

    (2006)
  • M. Benjamin et al.

    Evidence for a distinctive pattern of bone formation in enthesophytes

    Annals of the Rheumatic Diseases

    (2008)
  • J. Zochling et al.

    European league against rheumatism. ASAS/EULAR recommendations for the management of ankylosing spondylitis

    Annals of the Rheumatic Diseases

    (2006 Apr)
  • S. Garrett et al.

    A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis disease activity index

    The Journal of Rheumatology

    (1994 Dec)
  • C. Lukas et al.

    Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis

    Annals of the Rheumatic Diseases

    (2009 Jan)
  • D. van der Heijde et al.

    ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis

    Annals of the Rheumatic Diseases

    (2009 Dec)
  • J.J. Anderson et al.

    Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis

    Arthritis and Rheumatism

    (2001 Aug)
  • J. Brandt et al.

    Development and preselection of criteria for short term improvement after anti-TNF alpha treatment in ankylosing spondylitis

    Annals of the Rheumatic Diseases

    (2004 Nov)
  • J. Sieper et al.

    Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes

    Arthritis and Rheumatism

    (2008 Mar)
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      The mechanisms leading to bone formation and progression of SpA are still not well defined.8 Lories et al have suggested that inflammation and bone anabolic response, leading to ankylosing, are maintained in parallel,9 whereas Schett et al rather suggested that inflammation gradually decreases until active repair process is initiated, leading to ankylosis.10 Formation of bony spurs at the enthesis may occur by a process resembling endochondral ossification.11

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